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Central Station was built on the site of a former station known as Calhoun Street Station. Both stations were owned by the Illinois Central Railroad or its predecessors. Construction of Memphis Central Station began in September 1912, and the station was opened for service on October 4, 1914. The track design included five stub-end tracks (station tracks 1-5), and five through tracks (station tracks 6-10).

Like other large stations across America, the rapid decline of the passenger train network in the 1960s made Memphis Central Station an aging, nearly deserted monument to an earlier era. Rock Island passenger train service to Memphis ended in November 1967, and Frisco train service ended a month later, leaving Illinois Central as the sole occupant of the station. On May 1, 1971, nearly all passenger trains in the United States were handed over to Amtrak, which began operating a single train through Memphis, and large sections of Central Station were closed off and abandoned. Illinois Central offices were moved from the station, and it appeared that the station would eventually be razed, facing the same fate as Memphis Union Station.

After falling into disrepair, Memphis Central Station gained a reputation as one of the worst stations on the Amtrak system. The property was eventually acquired by Memphis Area Transit Authority, and a massive renovation project was undertaken. Much of the former waiting room area of the station would become public meeting area, the Illinois Central office space on upper floors was converted to condominiums, and Amtrak retained a smaller presence in the former midway area of the station. The station renovation, which was completed in November 1999, helped to speed the renovation and redevelopment of this once deserted area of downtown Memphis.

In anticipation of the landfall of Hurricane Gustav, the city of New Orleans began evacuating residents without the means to leave the city, starting on August 30, 2008. One thousand twenty-four evacuees arrived in Memphis via Amtrak.[2]